Summary for lncR MEG3-4 Gram-negative bacteria are important human pathogens that cause high morbidity and mortality, and their increasing antibiotic resistance presents daunting challenges to healthcare. Furthermore, aberrant host defense including excessive inflammatory responses causes detrimental effects following infection, resulting in uncontrollable sepsis and severe outcomes. Long noncoding RNAs (lncRNAs) are important regulators of gene expression; however, their functions in inflammatory responses to bacterial infection are poorly understood. We used a screening approach to identify the lncRNA MEG3-4 as a tissue-specific modulator of inflammatory responses during pulmonary bacterial infection. We also discovered a novel role for microRNA-138 in regulating inflammation through a critical interaction with the lncRNA MEG3-4. Importantly, we revealed a novel mechanism by which MEG3-4 functions as a competing endogenous RNA that binds miR-138 and releases the miRNA's target, IL-1? mRNA. This in turn intensified the inflammatory responses in both cells and mice. These exciting findings prompted us to further dissect the decoy modulation mechanism of lncRNAs in anti- bacterial immunity, as well as assess the impact on phenotype and disease progression in a sepsis model following Pseudomonas aeruginosa infection. We hypothesize that downregulation of MEG3-4 will mitigate Pa infection by soothing the inflammatory response. To test this hypothesis, we propose the following three specific aims: 1, To define the role of MEG3- 4 in host defense against bacterial infection in a tissue-specific manner; 2, To study the molecular mechanisms by which MEG3-4 regulates the inflammatory response against infection; and 3, To determine whether repression of MEG3-4 in critical cell populations will soothe inflammation and help control infection. Completion of this research will dramatically expand our knowledge of the role of lncRNAs and the associated regulatory pathways, which will benefit the pharmaceutical community in their desparate search for new bacterial therapeutics against multidrug resistant strains.